Vitamins are organic molecules that mainly function as co-factors associated with enzyme catalysts for reactions within the body. Vitamin c (ascorbic acid) is a water soluble vitamin that is necessary for normal growth and development. Human beings require dietary vitamin c for the prevention of scurvy. Vitamin c is found mostly in fruits and vegetables. It is also available on the market as an over the counter preparations or as for prescription use only. Beside all the important functions of vitamin c, the participation in collagen synthesis seems to be the most important one. Clinically, it is used to prevent and alleviate the symptoms of scurvy and to acidify the urine. The recommended dietary intake for vitamin c is set to be 75mg/day for women and 90mg/day for men with an additional 35mg/day for those who smoke. Vitamin c deficiency can lead to serious problems like scurvy which is considered to be the worst. There is a long standing controversy regarding the effectiveness of megavitamin therapy to treat or prevent disease, and there is much disagreement as to the potential benefits .The proponents of vitamin c therapy claim that mega doses of the vitamin have various benefits and uses, while others claim that there is no point in consuming such large doses. Each side has presented many arguments in support of their position. More over, there have been many different arguments about using vitamin c as a nutritional supplement to maintain general health.

In conclusion, Vitamin c is a very essential and important vitamin that should be contained in our diets, and it has many roles and uses.

Introduction

With increased public nutritional awareness, there has been a growing popular trend to consume high doses of vitamins and minerals and other biomolecules in the belief that this increases health and reduces risk of disease. This project will discuss some of the major issues and views regarding the intake of very high doses of vitamin c.

The project will give a brief description of the vitamin and the various formulations in which it is available. It will describe the mechanism of action and cellular function of the vitamin. The clinical and nutritional uses of vitamin c as well as the recommended dietary intake will be discussed. The effect of vitamin c deficiency will also be described. Moreover, there will be an evaluation of the evidence and the claims for the effectiveness of megavitamin therapy in the treatment or prevention of diseases. Finally, the arguments for using vitamin c as a nutritional supplement to maintain general health will be evaluated.

(1) Description of the vitamin and the available formulations :

The word vitamin is derived from the combination of words: vital amine. Vitamins are organic molecules that mainly function as co-factors associated with enzyme catalysts for reactions within the body. (1). Vitamin c, (ascorbic acid), is a water soluble vitamin that is necessary for normal growth and development.(2, 3). It is a six-carbon ketolactone structurally related to glucose and other hexoses. It is reversibly oxidized in the body to dehydroascorbic acid; which possesses the full activity ascribed to vitamin c. (4).

Human and other primates as well as guinea pigs and some bats are unable to synthesize ascorbic acid and require dietary vitamin c for the prevention of scurvy. Animals that do not require supplementation synthesize ascorbic acid from glucose. Humans lack the hepatic enzyme that is required for ascorbic acid synthesis from glucose. (4).

Vitamin c is found mostly in fruits and vegetables, where the highest concentrations are in fresh, raw foods, while whole grains, seeds or beans contain very little vitamin c, except when they are sprouted, which raises the ascorbic acid content. (See appendix 1 for details (5)). Similarly, animal foods contain almost no vitamin c, although raw fish has enough to prevent deficiency symptoms. Cooking can destroy much of the vitamin c content in food, and it is easily oxidized in air and sensitive to light. Being mostly contained in the watery part of fruits and vegetables, vitamin c is easily lost during cooking in water, so the steam cooking of vegetables minimizes its loss. (6).Vitamin c is available in the following forms and strengths for over the counter (OTC) use:

* Capsules: 100 mg, 250 mg, 500 mg, 1000 mg.

* Capsules, Extended Release: 500 mg, 1000 mg.

* Cream: 10% w/v.

* Chewable Tablets: 60 mg, 100 mg, 200 mg, 250 mg, 500 mg, 1000 mg.

* Liquid: 100 mg/ ml, 500 mg/ 5ml.

* Lozenges: 25 mg.

* Syrup: 500 mg/ 5 ml.

* Tablets: 100 mg, 250 mg, 500 mg, 1000 mg.

* Tablets, Extended Release: 500 mg, 1000 mg, 1500 mg, 2000 mg. (7).

It is also available for prescription (Rx) use by:

* Injection: 222 mg/ ml, 250 mg/ ml, 500 mg/ ml.

The various forms of vitamin c available in the market are due largely to marketing and commercial purposes and reflect the need to cater for a wide range of individual preferences for the route of intake. Additional benefits of the different formulations of vitamin c will be highlighted later in the discussion on supplementation.

(See appendix 2 for vitamin c formulations (8)).

(2) Mechanism of action and cellular function :

Vitamin c functions as a cofactor in a number of hydroxylation and amidation reactions by transferring electrons to enzymes that provide reducing equivalents. So, it is required for the conversion of certain prolines and lysine residues in pro-collagen to hydroxyl proline and hydroxyl lysine in the course of collagen synthesis. Collagen is an important protein constituents of skin, scar tissues, tendons, ligaments, and blood vessels. Ascorbic acid promotes the activity of an amidating enzyme thought to be involved in the processing of certain peptide hormones such as oxytocin, anti diuretic hormone, and cholecystokinin. Vitamin c helps in the conversion of folic acid to folinic acid. It also promotes the intestinal absorption of iron by reducing non-heme ferric iron to the ferrous state. (4). More over, vitamin c is essential for the healing of wounds and for repair of cartilage, bones, and teeth. (2). It is also important because it helps in protecting the fat soluble vitamins A and E as well as fatty acids from oxidation. (1).

At the tissue level, ascorbic acid is involved in the synthesis of collagen, proteoglycans, and other organic constituents of the intercellular matrix of several tissues as teeth, bones and capillary endothelium. In collagen synthesis it is required for the hydroxylation of proline to hydroxyl proline and hydroxylysine. There is evidence suggesting that ascorbic acid has a direct stimulatory action on collagen peptide synthesis.

(3) Clinical and nutritional uses and recommended dietary intake :

Clinically, vitamin c is used to prevent and alleviate the symptoms of scurvy, and to acidify the urine. It also can be beneficial in the treatment of iron deficiency anemia.

Scurvy is associated with a defect in collagen synthesis that is apparent in the failure of wounds to heal, defects in tooth formation, and rupture of capillaries. About100- 250 mg one to two times per day for at least two weeks can be given orally, intramuscularly (I.M), intravenously (I.V), or subcutaneously ( S.Q) for treatment of scurvy (9).

For urinary acidification, 4-12 g/ day in 3-4 divided doses is given orally, or by I.V.

There is unlabelled/ investigational use of the vitamin in large doses of 1-3 g/ day to decrease the severity of cold symptoms. A twenty year study was recently completed involving 730 individuals who indicate a possible decreased risk of death by stroke when vitamin c at doses ≥ 45 mg/ day was administered. (9).

Vitamin c is given orally as 5-200 mg/ day as a dietary supplement.(9).

Recommended dietary allowance (RDA) is defined as the average daily dietary intake level that is sufficient to meet the nutrient requirement of nearly all healthy individuals in a group. (3). The best way to get the daily requirement of essential vitamins is to eat a balanced diet that contains a variety of foods from the food guide pyramid. (Appendix1 (5)). In the past, determining recommended daily intakes was not an accurate science. It was very difficult to identify the ideal intake for optimum health as individual life styles vary so greatly (10). Recently, based on the vitamin's role as an antioxidant and to avoid deficiency, the official recommended daily intake of vitamin c has been set as 75 mg/ day for women and 90 mg/ day for men. Individuals who smoke cigarettes are encouraged to consume an additional 35 mg/ day of the vitamin than non-smoking adults. This is due to the fact that smoking depletes vitamin c levels in the body and is a catalyst for biological processes which damage the cells. (1).

Although high intakes of the vitamin are generally well tolerated, an upper level was recently set as 2 g/ day based on gastrointestinal upset that sometimes accompanies excessive dosages (11, 12).

The recommended daily intakes (RDI) of dietary vitamin c according to the World Health Organization (WHO) are: (9)

In its severe form, vitamin c deficiency leads to scurvy, which is mainly found in older malnourished adults or those with very restrictive diets lacking fresh fruit, vegetables, etc.(2).

Since vitamin c plays a major role in the synthesis of collagen, a deficiency will cause breakdown of the collagen protein needed for connective tissue, bones and dentin; (the major portion of the teeth). Collagen is involved in cell adhesion, and is an essential part of the connective tissue. Whenever the body in injured, collagen is formed during the repair process to form a scar. A lack of collagen causes breakdown of capillaries leading to hemorrhage. The loss of collagen from capillaries leads to increased symptoms of scurvy. Deficiency generally leads to weakness and pain in the joints. Internal hemorrhage causes black and blue marks to appear on the skin. At the first visible signs of scurvy, raised red spots appear on the skin around the hair follicles of the legs, buttocks, arms and back. When the tiny capillaries of the hair follicle hemorrhage, the hair producing cells are deprived of the nourishment needed for the hairs to grow normally. Consequently, the skin becomes flecked with small lesions that begin to appear on the body after several months on a diet deficient in vitamin c. Gums hemorrhage and their tissue becomes weak and spongy. Dentin, which lies below the enamel and is part of the root of teeth, breaks down. Teeth loosen and eating becomes difficult and painful. (13).

5- Effectiveness of megavitamin therapy to treat or prevent disease :

There is a long standing controversy regarding the effectiveness of megavitamin therapy to treat or prevent disease, and there is much disagreement as to the potential benefits. The proponents of vitamin c therapy claim that mega doses of the vitamin have various benefits and uses, while others claim that there is no point in consuming such large doses. Each side has presented many arguments in support of their position.

The group claiming that mega doses are beneficial has proposed several uses and supports each with an explanation. Professor Frederick Robert Klenner, a clinician in the Pauling's Institution, belongs to this group. Based on his clinical experience, he said that ascorbic acid must be given for burns treatment in frequent intravenous injections. He claims to have used about 30- 100 g/ day continuously until healing takes place; 7-30 days, depending upon the degree of severity of the burn. These high doses of ascorbic acid are also claimed to remove the smoke poisoning found in many fire victims, especially children who are more susceptible to the effects of toxic gases.

More over, he said that herpes simplex virus and adenovirus can be destroyed with high doses of ascorbic acid. He also claimed that many infections can be prevented by taking daily amounts of vitamin c by mouth of up to 1 g for each year of life up to age 10, and that after 10 years of age at least 10 g of the vitamin should be taken daily. Klenner believed that white blood cells are useless unless they have a high concentration of ascorbic acid, since it improves their phagocytotic ability and or destructive action against pathogens. Although herpes simplex infection usually shows itself as small lip sores and the adenovirus as mild cold, both can become killers through passage of the virus to the brain. (14).

Klenner also claimed that when taking ascorbic acid in sufficient amounts the intraocular pressure will be relieved in patients with glaucoma. Also when the vitamin is given by injection, (I.V, or I.M), it will destroy all viruses, and many can be destroyed by taking 25- 30 g daily by mouth. In addition, he claimed that he had cured diphtheria, hemolytic streptococcus and staphylococcus infections by giving vitamin c intravenously in doses ranging between 500- 700 mg/ kg body weight. He said that doses under 400 mg/ kg body weight can be given by a syringe using the sodium salt. This will produce thirst. Fluids taken just before or immediately after will eliminate this problem. He also said that doses above 400 mg/ kg body weight must be diluted to at least 1 g to 18 cc solution, using 5% dextrose in water, saline or Ringer's solution. His advice was to add 1 g calcium gluconate to these bottle injections to replace calcium ions pulled from the calcium- prothrombin complex. "There is no limit to the amount that can be administered intravenously when considering these precautions" said Klenner (14). One point to mention here is that Klenner didn't state clearly how often these amounts should be given.

He also stated that vitamin c is a positive neutralizing agent in snake bite, spider bites, and inset sting. But the use of ascorbic acid in snake bites was limited to the High land moccasin; a member of the copperhead family. "Other poisonous snakes are more deadly but I can easily calculate from my experience what dose to employ" he said. In a 4 year old receiving a full strike from a mature High land moccasin, 12 g of vitamin c were required to protect him.

''Ascorbic acid can be life saving in shock'' said Klenner. He claimed that 12 g of the sodium salt given with a 50 cc syringe will reverse shock in minutes. Not only that, but also 10- 12 g in the preoperative solutions and 10 g in each postoperative bottle will eliminate surgical deaths and will reduce hospital stay by 50%. The same can be said for obstetrical cases. He found that obstetrical cases needed 4 g each day in the 1st trimester, 6 g in the 2nd trimester, and 8- 10 g in the 3rd trimester (14).

"Vitamin c is the safest and the most valuable substance available to the physician". Many heartaches and headaches can be avoided with its proper use according to Klenner. (14).

Patrick Holford is another doctor from the same institution (Vitamin C Foundation), supporting the megavitamin theory. Based on his clinical experience (15), he believed that the immune system depends on having healthy immune cells and antibodies, and vitamin c is essential for both. "Ascorbic acid is also needed for interferon and prostaglandin production and is important for the function of lymphocytes and leukocytes", he said. Moreover, he supported the claims of the Nobel laureate Linus Pauling, in that 10g /day of vitamin c doubles the life expectancy of cancer patients, and in some cases effects a complete cure. He also said that its effect is more vital in cardiovascular diseases. Holford claimed that "adequate" intake of vitamin c at levels up to 10 g per day improves almost all cardiovascular markers. Furthermore, he claimed that vitamin c increases resistance to stress, lessens allergic reactions, helps arthritic conditions, slows down the aging process and improves energy production.

Robert Cathcart also belongs to the group supporting megavitamin c intake (again from the same Foundation). He believed that the ideal intake of the vitamin for any individual is the highest level he can tolerate without loose bowels. On the basis of his experience with 11,000 patients over 14 years, he said this level may be 10- 15 g/day in a healthy person, 30- 60 g/day in a person with a cold and over 199 g/ day in a person with serious infectious disease. He said that during an infectious illness, maintaining 3 g or more of vitamin c levels in the blood by frequent intakes will give the best clinical results. (14).

At the most recent meeting of the AmericanCollege for Advancement in Medicine, Hugh Riodran, of the Center for the Improvement of Human Health Functioning International in Wichita, Kansas, gave an extremely provocative presentation on the use of intravenous vitamin c as a treatment for cancer and other diseases. He said that high blood concentrations of vitamin c can kill cancer cells and microbes, but are non-toxic to healthy cells. During the past 28 years, Dr. Riordan has used I.V vitamin c (15- 100g) to treat bacterial and viral infections, relieve toxic reactions to insect bites, and improve the quality of life for people with cancer ( in some cases entirely eliminating their tumors). (16)

Dr. Julian Whitaker, author of Health and Healing supports the claims of Riordan, Cathcart and Klenner. Moreover, he says that at the Whitaker Wellness Institute, they used I.V vitamin c (up to 75 g) for over 20 years, with no sign of toxicity. What's more, is that I.V vitamin c therapy can be administered at home, and Riordan himself sends many of his patients home, and a nurse comes by simply to mix the solution and hook up the I.V. (16)

In addition to these very controversial claims, recent more "controversial" research has indicated that the intake of antioxidants like vitamin c can prevent or counteract cell damage due to aging, exposure to antioxidants and cancer. However, it has yet to be convincingly demonstrated that vitamin C's effectiveness at the cell level translates to the prevention of or cure of chronic diseases.

High doses of vitamin c taken at the beginning of a cold have been shown only in some cases to reduce the severity of the symptoms to a modest degree, due to a mild antihistaminic effect. Vitamin c has not been commonly shown to prevent the common cold as Pauling had claimed. Similar high doses of vitamin c used for the treatment of cancer patients (according to Pauling's claims) have not been found to be beneficial. For example, research done at the Mayo Clinic in a double blind trial (neither the doctors nor the patients knew who was given the high doses of vitamin c) showed that those who received the vitamin in the large dosage actually did worse than those who received a placebo (1). Dr. Stephen Barrett presented a paper on November 7, 1999 explaining the details of the Mayo Clinic studies and the mistakes in Pauling's own studies and subsequent claims (17). He said that Pauling and Ewan Cameron had claimed that patients treated with high doses of vitamin c had survived three to four times longer than similar cancer patients who did not receive vitamin c supplements at large doses.

Stephen Barett, and the Mayo Clinic studies, disagrees with the claims of Pauling and Cameron. He reasoned that their study was not a clinical trial in which patients were compared to carefully matched patients chosen at random and followed using a standardized protocol. Instead, he says, Pauling and Cameron attempted to reconstruct what happened to the control group by examining their medical records. Most cancer specialists and journal editors are extremely reluctant to accept this type of study for evaluating the validity of contemporary cancer therapy, primarily because bias may occur in selecting controls.

In 1978, the Mayo Clinic embarked on a prospective, controlled double-blind study designed to test Pauling and Cameron's claims. The results are noteworthy. About 25% of patients in both groups showed some improvement in appetite, 42% on placebo alone experienced enhancement of their level of activity. About 40% experienced mild nausea and vomiting. There were no survival differences between patients receiving vitamin c and those receiving the placebo. Overall, the study showed no benefit from high dose vitamin c.

In the second study of the Mayo Clinic, there was also no apparent benefit from treatment with high dose vitamin c. Following publication of the results obtained from these two studies, some commentators suggested that the study patients might not have been representative of cancer patients as a whole, that perhaps there was a subtle selection or referral bias that may have skewed the results. So a third prospective, randomized, stratified study was conducted under the auspices of the North Central Cancer Treatment Group, an international, multi-institutional, collaborative oncology group. Based primarily at the Division of Oncology at the Mayo Clinic, the group also had input from community-based cancer specialists in the Upper Midwest, Louisiana, Montana, Pennsylvania, and Saskatchewan, Canada. The study found that the vitamin c group survived no longer than the placebo group. One point to mention is that the data showed something that was intriguing. At two weeks after the onset of therapy, some patients receiving vitamin c experienced substantial improvement in appetite, strength, and pain relief. However, these advantages quickly dissipated so that by 4-6 weeks, no meaningful advantage from vitamin c remained.

The researchers concluded that vitamin c had provided transient symptomatic improvement in appetite and strength for a small proportion of treated patients. However, survival was not enhanced by vitamin c. To summarize, three prospectively randomized, placebo-controlled studies involving 367 patients documented no consistent benefit from vitamin c among cancer patients with advanced disease. Moreover, high doses of vitamin c can have significant adverse effects. High oral doses can cause diarrhea, while high intravenous dosage has been reported to cause kidney failure due to clogging of the kidney tubules by oxalate crystals. (17).

6- Arguments about vitamin c supplementation to maintain general health:

Why do some people maintain good health without supplementation?

If one analyzes people living to a ripe old age in reasonable health without the help of any supplements, one finds that they had many things in their favor. What happens is that a person starts his life healthy with no gene mutations or defects, and then he tends to lack some factors due to an accident or a disease. These factors are necessary to maintain the body chemical balance which in part is responsible for general health. So, as a result his life quality will be affected and he may require compensation through extra nutritional support or drug intervention. A centenarian who never touched a supplement in his life has likely maintained such a balance as a result of little "pro-oxidant" activity, which necessitated little "antioxidant" activity.

On the other hand, let's assume a very healthy individual with longevity odds in his favor ends up with a serious injury early in his life. The imbalance introduced to his previously sound chemistry by drug treatments or organ damage will have him for the rest of his life search for compensatory factors to improve the quality of life. Unlike before his injury, he is now in the same situation as those born less fortunate health-wise, and may now have to become more reliant on better nutrition and/or additional supplementation. So the reason for supplementation and the amounts needed change with individual circumstances. Even without previous injury, there are enough genetic variations or environmentally introduced factors that are responsible for some people to benefit from ingesting several grams of ascorbic acid per day, in contrast to those requiring no additional intake of supplements. The most common reason is that they likely exhibit excessive levels of vitamin c antagonists, or factors that inhibit vitamin c activity. Of those, the most common one is copper, but there are others, such as excessive levels or intake of zinc, calcium, magnesium, or very low levels of nickel, which supports vitamin c. People with very high copper levels rarely reach optimum levels of vitamin c unless they take in excess of 1 g/ day or unless they lower copper levels by other means. (6)

Ascorbic acid lowers zinc directly and indirectly by supporting iron uptake. So while higher intake of vitamin c would likely be beneficial for those suffering from some forms of anemia, leukemia, left-sided ovarian cysts, or from prostatitis, it could compromise patients with benign prostatic hypertrophy, and certain liver conditions.

Larger amounts of vitamin c lower manganese levels and this aids greater insulin production in those capable of producing insulin, which may be beneficial in type two diabetics, but it would worsen those with hypoglycemic tendencies. By lowering manganese, vitamin c affects glycogen stores in the liver, decreasing the liver's ability to store larger amounts. Manganese influences the liver's ability to break down estrogen, so too much vitamin c can affect the length of the menstrual cycle and worsen some types of post menopausal syndrome.

Calcium metabolism is very much affected by vitamin c intake. For patients who suffer from calcium overload, larger amounts of vitamin c are an effective part of the daily regimen to keep calcium soluble and prevent it from calcifying soft tissues. Appropriate (in the RDA range) amounts of vitamin c increases bioavailability of calcium levels, while very high intake of ascorbic acid (>5 g) will eventually put extra demands on calcium stores (bone) to make up calcium loss. This problem can be overcome using buffered vitamin c, such as calcium ascorbate or sodium ascorbate. More over, supplementing small amounts of nickel will reduce vitamin c requirements considerably, hence, the effects of the large amounts of vitamin c on the body (such as lowering calcium) will be reduced, and also it will reduce the need for the ascorbate form of the vitamin which might not be available in some areas around the world. In addition, vitamin E and vitamin C exhibit synergistic antioxidant activity, so when increasing the amounts of one also increases the requirements for the other (6).

More over, when discussing vitamin c supplementation, not all the news is positive. Commonly seen as a skin nutrient, some evidence indicates that vitamin c may in fact be the opposite when taken in excess, although the literature is contradictory on this point. So, unfortunately, many people are taking vitamin c in excess thinking that they are protecting their skin from harmful radiations. But the truth is that they are wasting a lot of their money because there is still no hard evidence that supports this use. (18).

So, Should one supplement with vitamin c or not?

The difference between healthy people who supplement vitamin c and other basic nutrients, and healthy ones who don't can perhaps be compared to younger versus older people facing the same medical condition. Younger people tend to handle medical situations better, or recover faster than older ones. Supplementing may perhaps be compared to effectively "lowering"biological age.

The above graph illustrates what percentage of the population will enjoy optimal benefits from vitamin c supplementation- not including the dietary sources of the vitamin. These amounts are based on average, cellular requirements of vitamin c, which go beyond the recommended dietary allowance (RDA/RDI). Instead, they consider the synergistic and antagonistic effect of all other nutrients that interact with vitamin c as well, to encompass a much wider scope of disease prevention. However, even optimal requirements tend to fluctuate under specific medical circumstances and may need to be adjusted. (6).

In addition, when talking about vitamin c supplementation, we must not forget that there are a large number of vitamin c formulations on the market. The label by law should accurately represent the contents. However, we should not necessarily take this for granted. It is important to read the label carefully.

A watchdog group (19) in the U.S has done recent tests and studies of 26 brands of vitamin c supplements. It found that 15% of them did not contain as much vitamin c as was listed on the label. Some of the products that flunked the test had more than 90% of the listed amount. What's more is that industry experts say that FDA has authority, but not the resources, to test the accuracy of every such product sold today in the U.S.A. Not only that, but also the standards set by the FDA and the United States Pharmacopoeia vary on how closely the actual product amounts must match the amount given on labels. Neither organization tests vitamin c products regularly (19). Their efforts are devoted to run refutation of drugs and 'food supplements' or nutraceuticals slip easily through their net.

The consensus of opinion seems to be that vitamin c is an important part of a healthy diet. It is not a miracle drug, and may cause harm if taken in extreme excess (more than 5g). A well- balanced, varied diet will ensure that you receive more than enough vitamin c to prevent scurvy and other potential health problems (1) due to vitamin c deficiency.

In conclusion, Vitamin c is a very essential and important vitamin that should be contained in our diets, and it has many roles and uses. There was and still is a big controversy among scientists and doctors about this vitamin and its clinical uses. Moreover, a lot of people consume large amounts of this vitamin in the belief that this increases health and reduces risk of disease, but to date there is still no hard evidence to support all of the claims that have been made about vitamin c. People should be better advised to pay more attention to their diets and try not to be fooled or tricked by commercial companies that try to sell their products with claims that actually have very little scientifically proven basis.

Indeed it seems that most of the 'evidence' for the use of vitamin c megadose therapy comes from a single source, the Linus Pauling Foundation.